Tetraydro-1-benzazepines and tetrahydro-1,4-benzodiazepines form the core structure of a variety of pharmaceutically useful compounds. In particular, WO 93/00095 (PCT/US92/05463) and WO 94/14776 (PCT/US93/12436) disclose 7-aminocarbonyl tetrahydro-1-benzazepines and tetrahydro-1,4-benzodiazepines which are reported, to be inhibitors of the fibrinogen and vitronectin receptors and useful as inhibitors of platelet aggregation, osteoporosis, angiogenesis and cancer metastasis.
Methods to prepare such compounds typically employ a trisubstituted phenyl derivative as a starting material. The trisubstituted phenyl derivative incorporates two substituents to form the azepine ring, and a third substituent to introduce the 7-carbonyl substituent. Such starting materials may be difficult and costly to obtain, and may limit the chemistry which may be employed to form the azepine ring,. Prior processes generally introduce the aminocarbonyl group into the molecule via a 7-carboxyl group which is coupled to an amino group by conventional methods for forming amide bonds. Methods disclosed in WO 93/00095 and WO 94/14776 are exemplary.
We have now discovered new useful intermediates and a new process for preparing certain substituted 7-aminocarbonyl benzazepines and benzodiazepines. The new process uses a simple disubstituted benzene as a starting material, and also introduces the aminocarbonyl function in a single palladium catalyzed aminocarbonylation step. This process is more efficient than prior processes for preparing such compounds and adaptable to large scale synthesis.
Various types of palladium catalyzed reactions with aryl and vinyl halides are known to the art, and the problems attendant to their use with electron rich systems have been studied. For instance, Ziegler et al., J. Org. Chem. 1978, 43, 2941, report that highly activated aryl bromides, such as bromo-anilines, reacted very poorly in palladium catalyzed vinylic substitution reactions, but observed that some improvement was noted when aryl iodides were used, and when the palladium ligand was an tri-o-tolyl phosphine rather than a triphenylphosphine. Cortese et al., J. Org. Chem. 1978 43, 2952, report a palladium catalyzed vinylic substitution reaction on an o-iodo aniline.
Valentine et al., J. Org. Chem. 1981, 4614, suggest that the unreactivity of o-bromo-anilines toward carbonylation may be overcome by acetylation of the anilino amine group. Kraus et al., Tet. Lett. 1994 49, 9189 disclose an alkoxycarbonylation of a 7-triflic-tetrahydro-1,4benzodiazpine.
Heck et al., J. Org. Chem. 1974, 39, 3327, report typical conditions for aminocarbonylation reactions on aromatic systems; however, they do not report conditions for aminocarbonylation of electron-rich systems such as halo-anilines. Certain o-bromoanilines have been reported to undergo aminocarbonylation in low yield by Mori et al., Heterocycles 1981, 16 1491, and Perry, Chemtech Feb. 18, 1994 reports the use of iodo-aryl and amino-aryl monomers in a palladium catalyzed carbonylation reaction to prepare aramide polymers.